The roles of glucagon, glucose and insulin in the regulation of gluconeogenesis and the possible involvement of the fructose-6-phosphate (F-6-P) and phosphoenol-pyruvate (PEP) cycles in this process are being investigated. (3-3H,6-14C) glucose is administered in vivo and the 3H/14C plasma glucose ratio is used as an index of F-6-P substrate cycling since the amount of detritiation is determined by its activity. PFK and FDPase activities limit 3H loss during gluconeogenesis and glycolysis respectively. (1-3H) galactose is also used to examine F-6-P cycling since this labeled sugar exclusively enters the liver and upon conversion of F-6-P labels the hexose phosphate pool. Cycling is determined by measuring randomization of 3H from C1 to C6. Glucose formation will be simultaneously followed using (14C)alanine and correlated with F-6-P substrate cycling. Activity of the PEP substrate cycle will be investigated using (6-3H,6-14C) glucose. Experiments will also be carried out to investigate the role of growth hormone (GH) in the regulation of liver glutamine synthetase (GS) activity and the relationship of this action to the hormone's action in increasing gluconeogenesis. GH increases glucose synthesis from amino acids while also decreasing nitrogen excretion. Liver GS may divert alpha-amino nitrogen away from urea synthesis to glutamine where it can act as a nitrogen away from urea synthesis to glutamine where it can act as a nitrogen donor for GH enhanced RNA, DNA, proteoglycan synthesis, etc.